DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group (I) with the addition of the compound-If
PNG
media_image1.png
270
288
media_image1.png
Greyscale
in the reply filed on 10/07/2024 is maintained. Please note the statement “however, it is noted that the elected compound of the formula (If) does not read on any of the present” under the Election/Restrictions section of the non-final action dated 05/02/2025 is an error, because the second rejection under 35 U.S.C 103 confirms that the elected species reads on the present claims 1, 6, 7, 12, and 13. Said error is rectified in this action. It is noted that the elected compound of the formula (If) does read on the present claims 1, 6, 7, 12, and 13. Therefore, for purpose of prosecution, the election of species has been expanded to the compound of the formula (I) in addition to the elected compound species.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed applications:
Application No. PCT International Application No. PCT/US2020/047791, filed on August 25, 2020;
U.S. Provisional Application No. 63/007,653, filed on April 9, 2020;
U.S. Provisional Application No. 63/053,976, filed on July 20, 2020;
U.S. Provisional Application No. 63/139,976, filed on January 21, 2021; and
U.S. Provisional Application No. 62/891,388, filed on August 25, 2019 provides adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. However, the elected compound (If)
PNG
media_image1.png
270
288
media_image1.png
Greyscale
is only described in the prior filed Application No. PCT International Application No. PCT/US2020/047791, filed on August 25, 2020, in the U.S. Provisional Application No. 63/053,976, filed on July 20, 2020, and the U.S. Provisional Application No. 63/139,976, filed on January 21, 2021. The elected compound species is not described in the U.S. Provisional Application No. 62/891,388, filed on August 25, 2019 and in the U.S. Provisional Application No. 63/007,653, filed on April 9, 2020. As such, the priority date of on July 20, 2020 is given to claims 1, 6, 7, and 12-13 with respect to the elected compound. The priority date for claims 1-4, 6, 7, 12, and 13 as it pertains to the expanded compound species is 08/25/2019.
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on September 14, 2025.
Applicant argues that compound (If) fails under the genus of formula (I) in at least U.S. Provisional Application No. 63/007,653, filed on April 9, 2020 and is explicitly disclosed as an exemplary compound in at least PCT International Application No. PCT/US2020/047791, filed on August 25, 2020.
In response, Applicant’s argument is not persuasive. It may well be true that compound (If) is explicitly disclosed as an exemplary compound in at least PCT International Application No. PCT/US2020/047791, filed on August 25, 2020. However, compound (If) is not disclosed in U.S. Provisional Application No. 63/007,653, filed on April 9, 2020. Moreover, just because compound (If) falls under the genus of formula (I) in at least U.S. Provisional Application No. 63/007,653, filed on April 9, 2020 does not mean the species of compound (If) is supported. In fact, MPEP 2173.02 states “a specific species must be disclosed in the application as filed to have support for a patent claim covering that species. If the application only discloses a broader genus, a later claim to a specific species not originally disclosed will lack written description support and can be rejected.”
Claims Status
Claims 1-20 are pending. Claims 5, 8-11, and 14-20 are withdrawn. Claims 1-4, 6, 7, 12, and 13 are examined in accordance to the expanded compound species.
Action Summary
Claims 1-4, 6, 7, 12, and 13 rejected under 35 U.S.C. 103 as being unpatentable over CHADEAYNE (US2018/0221396 A1) in view of Bavadekar et al (European Journal of Pharmacology 590 (2008) 53–60) and Patani et al (Chem. Rev. 1996, 96, 3147−3176), are maintained.
Claims 1, 6, 7, 12, and 13 rejected under 35 U.S.C. 103 as being unpatentable over Chadeayne et al (Acta Crystallogr E Crystallogr Commun. 2020 Jul 3;76(Pt 8):1201–1205) in view of Patani et al (Chem. Rev. 1996, 96, 3147−3176) and Raymond et al (CA1040217 A), are maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1-4, 6, 7, 12, and 13 remain rejected under 35 U.S.C. 103 as being unpatentable over CHADEAYNE (US2018/0221396 A1) in view of Bavadekar et al (European Journal of Pharmacology 590 (2008) 53–60) and Patani et al (Chem. Rev. 1996, 96, 3147−3176).
Chadeayne teaches a composition comprising a first purified psilocybin derivative; wherein the first purified psilocybin derivative is chosen from [3-(2-Dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N,N-dimethyltryptamine, [3-(2-methylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N-methyltryptamine, [3-(aminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, [3-(2-trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, and 4-hydroxy-N,N,N-trimethyltryptamine; and
a second purified psilocybin derivative; wherein the second purified psilocybin derivative is chosen from [3-(2-Dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N, N-dimethyltryptamine, [3-(2-methylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-N-methyltryptamine, [3-(aminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, [3-(2-trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate, and 4-hydroxy-N, N, N-trimethyl tryptamine. (See claim 1.) Chadeayne teaches the composition can modulate neurotransmitter receptor for the treatment of psychological disorder. (See claims 82 and 102.) This teaching renders the composition of Chadeayne a pharmaceutical composition. The structure of 4-hydroxy-N, N, N-trimethyl tryptamine is a follow:
PNG
media_image2.png
168
256
media_image2.png
Greyscale
. The “4-hydroxy-N, N, N-trimethyl tryptamine” refers to a compound, and/or salts thereof. (See paragraph [0095].) The salts would inherently chemically have to be a pharmaceutically acceptable anion. Moreover, Chadeayne teaches the first purified psilocybin derivative is used with a serotonergic drug. (See paragraph [0023].) Examples of serotonergic drug includes but not limited to 4-Methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine
PNG
media_image3.png
176
278
media_image3.png
Greyscale
. (See paragraph 0250].) Furthermore, Chadeayne teaches excipients such as sodium lauryl sulfate, sucrose, alcohol, gelatin, polyvinylpyrrolidone, methionine, Vitamin E TPGS, dimethyl sulfoxide, tartrazine, polyethylene glycol, magnesium stearate, stearic acid, fumed silica, talc, magnesium carbonate, or benzalkonium chloride can be included in the composition. (See paragraph [0278].) Although Chadeayne does not teach sucrose, gelatin, and polyvinylpyrrolidone are pharmaceutically acceptable excipients sucrose, gelatin, and polyvinylpyrrolidone are pharmaceutically acceptable excipients as evidenced by the specification at paragraph [119].
Chadeayne does not teach the compound of the formula (I)
PNG
media_image4.png
258
294
media_image4.png
Greyscale
where R1, R2, and R3 are each C1-alkyl (methyl), R4 is a C1-alkoxy (methoxy), and R6, R7, R8, and R9 are each hydrogen, and X is a pharmaceutically acceptable anion.
Bavadekar teaches the methylation of the phenolic hydroxy group and replacement of the 4-methyl group of phentolamine with varying lipophilic substituents yielded bioisosteric analogs selective for the α2- versus α1-adrenoceptors. (See Abstract.) Moreover, Bavadekar teaches binding affinities of the methoxy-substituted bioisosteric phentolamine were greater than those of the hydroxy-substituted bioisosteric phentolamine analog at all six human α-adrenoceptor subtypes. (See Compounds 2 and 6, Fig. 1).
Patani teaches the ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties. In this review an attempt has been made to quantitate, in specific instances, physicochemical effects such as electronegativity, steric size, and lipophilicity and to correlate these values to the observed biological activity. (See second paragraph of the left column of page 3148.) Moreover, Patani teaches the widespread application of the concept of isosterism to modify biological activity has given rise to the term bioisosterism. As initially defined by Friedman, bioisosteres were to include all atoms and molecules which fit the broadest definition for isosteres and have a similar type of biological activity, which may even be antagonistic. More recently this definition has been broadened by Burger as “Compounds or groups that possess near-equal molecular
shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. (See fourth paragraph of the right column of page 3148.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound taught by Chadeayne in this case 4-hydroxy-N, N, N-trimethyl tryptamine by replacing the hydroxyl group with the methoxy group and combine said compound with a serotonergic compound to give Applicant’s claimed compound. One would have been motivated to do so, because not only Chadeayne teaches compound that are similar to the 4-hydroxy-N, N, N-trimethyl tryptamine, i.e.,
PNG
media_image3.png
176
278
media_image3.png
Greyscale
bearing a methoxy group at the same position where the hydroxyl group is attached, but because Bavadekar teaches binding affinities of the methoxy-substituted bioisosteric phentolamine were greater than those of the hydroxy-substituted bioisosteric phentolamine analog at all six human α-adrenoceptor subtypes, and also because Patani defines bioisosteres as compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties. One would reasonably expect the modified compound, i.e., having a methoxy group instead of a hydroxyl group, to have better metabolic stability due to the nature of the OH group.
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on September 17, 2025.
Applicant’s argument
Applicant argues that Bavadekar only focuses on phentolamine and fails to teach any sort of compound that is similar to or represents the claimed compound of formula (I). Phentolamine compounds of Bavadekar and the tryptamine compounds of the claimed invention have a different core structure. Patani discloses a general overview of bioiosterism with an emphasis on outlining bioisosteric replacements which have been used to advance drug development. See Patani, 3147-3148. However, Patani also fails to teach the claimed compound of formula (I). There is no teaching or suggestion in Patani to modify any of the compounds disclosed in Chadeayne, let alone specifically 4-hydroxy-N, N, N-trimethyl tryptamine, in any specific way in order to arrive at the claimed compound of formula (I). Further, there is no teaching or suggestion in Patani that modifying any of the phentolamine compounds of Bavadekar would result in the claimed compound of formula (I). None of the compounds disclosed in Patani are similar to or represent the claimed compound of formula (I) or the 4-hydroxy-N, N, N-trimethyl tryptamine compound of Chadeayne. A person of ordinary skill in the art would not be motivated to modify Chadeayne in view of Bavadekar or Patani.
Examiner’s answer
In response, Applicant’s argument is not persuasive. Just because phentolamine compounds of Bavadekar and the tryptamine compounds of the claimed invention have a different structure does not mean they are not bioisosteres. In fact, Patani defines bioisosteres as compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties. Furthermore, Chadeayne teaches compound that are similar to the 4-hydroxy-N, N, N-trimethyl tryptamine is
PNG
media_image3.png
176
278
media_image3.png
Greyscale
, i.e. 4-Methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine
PNG
media_image2.png
168
256
media_image2.png
Greyscale
and it is bearing a methoxy group at the same position where the hydroxyl group is attached to. In fact, Chadeayne teaches both 4-hydroxy-N, N, N-trimethyl tryptamine and 4-Methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine have serotonin receptor and adrenergic receptor modulatory effects. Bavadekar teaches binding affinities of the methoxy-substituted bioisosteric phentolamine were greater than those of the hydroxy-substituted bioisosteric phentolamine analog at all six human α-adrenoceptor subtypes. Patani defines bioisosteres as compounds or groups that possess near-equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties. Chadeayne does not disclose or use the term bioisostere for compounds 4-hydroxy-N, N, N-trimethyl tryptamine and 4-Methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine. However, Bavadekar clearly shows that methoxy group and the OH group on compounds 4-hydroxy-N, N, N-trimethyl tryptamine and 4-Methoxy-N-methyl-N-(1-methylethyl)-1H-indole-3-ethanamine are bioisosteres, which was not expressly recognized by Chadeayne. There is nothing in the definition of bioisostere in Patani stating that replacement of chemical moieties for others has to come from the same or similar compounds. Therefore, ne would reasonably expect the modified compound, i.e., having a methoxy group instead of a hydroxyl group, to have better metabolic stability due to the nature of the OH group.
Claims 1, 6, 7, 12, and 13 remain rejected under 35 U.S.C. 103 as being unpatentable over Chadeayne et al (Acta Crystallogr E Crystallogr Commun. 2020 Jul 3;76(Pt 8):1201–1205) in view of Patani et al (Chem. Rev. 1996, 96, 3147−3176) and Raymond et al (CA1040217 A).
Chadeayne teaches solid-state structures of the hydro-fumarate salts of two DMT analogues: N-ethyl-N-propyl-tryptamine and its hydrofurmuarate salt (I)
PNG
media_image5.png
436
806
media_image5.png
Greyscale
and N-allyl-N-methytryptamine and its hydro-fumarate salt (II)
PNG
media_image6.png
470
788
media_image6.png
Greyscale
and both compounds possess a protonated tryptammonium cation, and a hydrofumarate anion in the asymmetric unit. (See Abstract and left column of page 1202.) Moreover, Chadeayne teaches class of traditional psychedelics, as well as synthetic variants, have started to gain a great deal of interest as antidepressants and anxiolytics. (See last paragraph of page 1201.)
Chadeayne does not teach the elected compound.
PNG
media_image1.png
270
288
media_image1.png
Greyscale
. However, the key differences between compound (II) of the prior art and the elected compound lie between lie in the hydrogen atom of the ammonium cation and the anion as depicted below:
Elected Compound Prior Art compound
PNG
media_image7.png
204
326
media_image7.png
Greyscale
PNG
media_image8.png
470
788
media_image8.png
Greyscale
Patani teaches the ability of a group of bioisosteres to elicit similar biological activity has been attributed to common physicochemical properties. In this review an attempt has been made to quantitate, in specific instances, physicochemical effects such as electronegativity, steric size, and lipophilicity and to correlate these values to the observed biological activity. (See second paragraph of the left column of page 3148.) Moreover, Patani teaches the widespread application of the concept of isosterism to modify biological activity has given rise to the term bioisosterism. As initially defined by Friedman, bioisosteres were to include all atoms and molecules which fit the broadest definition for isosteres and have a similar type of biological activity, which may even be antagonistic. More recently this definition has been broadened by Burger as “Compounds or groups that possess near-equal molecular
shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties...”. The critical component for bioisosterism is that bioisosteres affect the same pharmacological target as agonists or antagonists and, thereby, have biological properties which are related to each other. (See fourth paragraph of the right column of page 3148.) Furthermore, Patani teaches fluorine and hydroxyl, amino, or methyl Groups as Replacements for Hydrogen (Grimm’s Hydride Displacement Law). (See page 3152, Section A.)
Raymond teaches quaternary ammonium salts having a pharmaceutically acceptable anion that can include iodide. (See lines 1-9 of page 2.) Moreover, Raymond teaches pharmaceutically acceptable anions have the advantage of enhancing stability of drug product. (See lines 12-17 of page 3.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the compound (II) taught by Chadeayne) by replacing the hydrogen atom on the ammonium cation with a methyl group and further replacing the hydrofumurate with the iodine anion taught by Raymond to give Applicant’s claimed compound. One would have been motivated to do so, because Patani teaches hydrogen as a bioisotere replacement for a methyl (Grimm’s Hydride Displacement Law) and also because Raymond teaches quaternary ammonium salts having a pharmaceutically acceptable anion that includes iodide can have the advantage of enhancing stability of drug product. One would reasonably expect the modified compound with enhanced stability that can elicit similar biological activity as taught by Chadeayne.
Applicant’s argument
Applicant argues as stated in the above priority section the priority date of at least claims 1-4, 6, and 7 as it pertains to the expanded species of the compound of formula (I) where R1, R2, and R3 are each a C1-alkyl (methyl); R4 is a C1-alkoxy (methoxy); R6, R7, Rs, and R9 are each hydrogen; and X- is a pharmaceutically acceptable anion is at least April 9, 2020, the filing date of U.S. Provisional Application No. 63/007,653. Therefore, the earliest priority date of claims 1-4, 6, and 7 is April 9, 2020, which predates Chadeayne et al.'s publication date and even the accepted and received dates. Thus, Chadeayne is not prior art to the claimed invention.
Examiner’s answer
In response, Applicant’s argument is not persuasive. It may well be true that the priority date of at least claims 1-4, 6, and 7 as it pertains to the expanded species of the compound of formula (I) where R1, R2, and R3 are each a C1-alkyl (methyl); R4 is a C1-alkoxy (methoxy); R6, R7, Rs, and R9 are each hydrogen; and X- is a pharmaceutically acceptable anion is at least April 9, 2020, the filing date of U.S. Provisional Application No. 63/007,653. However, as it relates to the elected compound of formula (If) and as stated in the above priority section, the elected compound (If) is only described in the prior filed Application No. PCT International Application No. PCT/US2020/047791, filed on August 25, 2020, in the U.S. Provisional Application No. 63/053,976, filed on July 20, 2020, and the U.S. Provisional Application No. 63/139,976, filed on January 21, 2021. The elected compound species is not described in the U.S. Provisional Application No. 62/891,388, filed on August 25, 2019 and in the U.S. Provisional Application No. 63/007,653, filed on April 9, 2020. As such, the priority date of on July 20, 2020 is given to claims 1, 6, 7, and 12-13 with respect to the elected compound. The priority date for claims 1-4, 6, 7, 12, and 13 as it pertains to the expanded compound species is 08/25/2019. Therefore, Chadeayne et al (Acta Crystallogr E Crystallogr Commun. 2020 Jul 3;76(Pt 8):1201–1205) is prior art to the claimed invention.
Conclusion
Claims 1-4, 6, 7, 12, and 13 are not allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JEAN P CORNET/Primary Examiner, Art Unit 1628
Prosecution Insights